Angiogenesis is the main cause of various eye diseases that lead to millions of cases of blindness worldwide every year. In particular, representative examples of various eye diseases caused by abnormal blood vessels comprise age-related macular degeneration, diabetic retinopathy, and glaucoma.
Age-related macular degeneration is a disease that refers to the collapse or destruction of the macula occurring with the aging process, and usually occurs in people over 50 years of age. This disease is classified into a non-exudative (dry) type, wherein accumulation of small waste called “drusen” causes macular atrophy and thus loss of visual function, and an exudative (wet) type, wherein exudate escaping from abnormal new blood vessels generated due to hypoxia of the retina and choroid, and accumulation of oxidative stress leads to macular edema, and repetition of this process causes permanent degeneration in visual cells and retinal pigment epithelial cell layers (RPE cell layers) of the macula and thus loss of vision. In particular, wet-type macular degeneration has a high frequency of incidence of blindness, and the prevalence thereof in Korea is estimated to be 37 per 10,000 people. The cause of macular degeneration has not been elucidated yet, but age is a known risk factor, and other notable environmental factors comprise smoking, hypertension, obesity, genetic predispositions, excessive UV exposure, low antioxidant concentrations in the blood and the like. Currently, treatment for wet-type macular degeneration mainly focuses on antibody injection therapy for vascular endothelial growth factors, and other treatments such as laser photocoagulation, photodynamic therapy and vitrectomy are known, but there is no complete treatment yet to date.
Diabetic retinopathy is a complication of the eye involving decreased visual acuity due to retinal microcirculation disorder upon peripheral circulatory disorder due to diabetes. In early stages, diabetic retinopathy cause no symptoms or only mild vision problems, but may ultimately lead to blindness. Diabetic retinopathy can occur in anyone having Type 1 or Type 2 diabetes.
Glaucoma is a chronic optic nerve disease, more particularly, a severe refractory disease that leads to loss of vision due to progressive degeneration of optic nerves, progressive loss of retinal ganglion cells and visual field defect. Various risk factors of glaucoma comprise age, race, gender and hypertension, but intraocular pressure elevation is known to be the most important cause of various kinds of glaucoma, especially primary open-angle glaucoma. Glaucoma is considered to be due to intraocular pressure elevation resulting from increased resistance of the aqueous humor drainage pathway passing through the Schlemm's canal and trabecular meshwork. However, the molecular biological mechanism causing the problems associate with the aqueous humor drainage pathway has not been verified to date. For the treatment of glaucoma, there are methods of using drugs for reducing the production of aqueous humor or laser trabeculoplasty, surgically forming a new aqueous humor drainage pathway and the like. However, conventional non-surgical treatment is incapable of solving aqueous humor drainage pathway abnormalities and thus the effects thereof are insufficient, and surgical treatment often results in clogging of the newly formed aqueous humor drainage pathway due to the normal tissue-healing reaction. Accordingly, there is no fundamental therapeutic method yet.
Angiopoietin-2 (Ang2) is an antagonistic ligand of the receptor Tie2 present in vascular endothelial cells and functions to suppress signal transduction by Tie2 by competing for binding Tie2 with angiopoietin-1 (Ang1), which is an agonist of Tie2. Ang1, which is the ligand that activates the Tie2 receptor, acts as a major regulator to maintain stability of vessels by maintaining the barrier function of vascular endothelial cells. In overexpression of vascular endothelial growth factors or inflammation, vascular endothelial cells are activated and vascular permeability is increased. At this time, Ang1 induces stabilization of vascular endothelial cells and reduces vascular permeability by promoting junctional integrity of vascular endothelial cells, while increased Ang2 in activated vascular endothelial cells functions to inhibit stabilization of the vascular endothelial cells by competing with Ang1. Thus, Ang2 inhibit Ang1-Tie2 binding and its signal transduction which maintain the stability of vascular endothelial cells, thereby promoting angiogenesis through the dynamic rearrangement of blood vessels. Overexpression of Ang2 in various solid cancers and blood cancers has been reported, and overexpression of Ang2 in various diseases such as sepsis, bacterial infection, lung damage and kidney damage has been reported.
In the prior art, Korean Patent Laid-open No. 10-2015-0014077 identified an anti-Ang2 antibody that specifically binds to angiopoietin-2 (Ang2), which is an angiogenesis-inducing factor, additionally binds to a Tie2 receptor together with Ang2, and/or has improved humanization ability and/or affinity, the use of such anti-Ang2 antibody as an anticancer agent (Korean Patent Laid-open No. 10-2015-0032075) and the use thereof in the treatment of sepsis (Korean Patent Laid-open No. 10-2015-0028087). However, there has been no experimental evidence on the use of the anti-Ang2 antibody for the treatment of eye diseases.
Therefore, the present inventors have made efforts to develop therapeutic agents for various eye diseases caused by abnormal blood vessels. As a result, the present inventors have found that an anti-Ang2 antibody specifically binding to Ang2 and binding to a Tie2 receptor together with Ang2 is effective in inhibiting vascular leakage and choroidal angiogenesis and in improving choroidal flow in a wet-type macular degeneration animal model, is effective in alleviating vascular leakage and inhibiting macrophage infiltration in a diabetic retinopathy animal model, and is effective in enhancing Schlemm's canal homeostasis and decreasing intraocular pressure in a glaucoma model. Based on this finding, the present invention has been completed.